Investigating the heterogeneity of alkylating agents’ efficacy and toxicity between sexes: A systematic review and meta‐analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study)
Year: 2017
Type: review
Study designs: Systematic Review, Meta-Analysis
Abstract: BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.
Source: Pediatric Blood & Cancer
DOI: 10.1002/pbc.26457
Institutions: Université Paris-Saclay, Institut Gustave Roussy, Cancer Research UK, University College London, Seattle Children's Hospital, University of Washington, Fred Hutch Cancer Center, Witten/Herdecke University, Merck & Co., Inc., Rahway, NJ, USA (United States), Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, European Organisation for Research and Treatment of Cancer, European Organisation for Research and Treatment of Cancer, University Hospital Münster, Alder Hey Children's NHS Foundation Trust, Alder Hey Children's Hospital, Amsterdam UMC Location University of Amsterdam, Emma Kinderziekenhuis, Leiden University Medical Center, University College Hospital, The University of Sydney, Cancer Research UK Clinical Trials Unit, University of Birmingham, Inserm, La Ligue Contre le Cancer, Centre de recherche en Epidémiologie et Santé des Populations
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'Adolescent, Cancer Research UK, European Commission, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Deutsches Zentrum für Luft- und Raumfahrt, Deutsche Krebshilfe, Institut Gustave-Roussy, Unicancer, National Cancer Institute
Awards: G1151979577, G1504112592, G1737400705, G1930807489, G2305489469, EUROPEAN NETWORK for CANCER research in CHILDREN and ADOLESCENTS, G2629711771, G2901481919, G359519136, Children's Oncology Group Statistics and Data Center, G4894623320, TRANSCAN I - Verbund: Prospektive Validierung von Biomarkern in Ewing Sarkomen (PROVABES), Teilprojekt Münster, G6009552911, Verbundprojekt Translationales Sarkom-Netzwerk (TranSaRNet): TP0: Koordination, TP2: miRNA-Expression in Osteosarkomen und mesenchymalen Stammzellen, TP3: Epigenetische Regulation in Sarkomen und mesenchymalen Stammzellen, TP6: Genom-weites Screening in Ewing Sarkomen, TP15: Biomaterial Bank, TP16: Bioinformatik, G6623372364, G8015775736, G889960032, G997771125
OpenAlex ID: W2581004021